Smooth Muscle Hypertrophy Research Articles

Fatal Cardiac Arrhythmia and Long-QT Syndrome in a New Form of Congenital Generalized Lipodystrophy with Muscle Rippling (CGL4) Due to PTRF-CAVIN Mutations

We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4) of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin) as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT). PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM) in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

Pulmonary artery smooth muscle hypertrophy: roles of glycogen synthase kinase-3β and p70 ribosomal S6 kinase

Increased medial arterial thickness is a structural change in pulmonary arterial hypertension (PAH). The role of smooth muscle hypertrophy in this process has not been well studied. Bone morphogenetic proteins (BMPs), transforming growth factor (TGF)-beta1, serotonin (or 5-hydroxytryptamine; 5-HT), and endothelin (ET)-1 have been implicated in PAH pathogenesis. We examined the effect of these mediators on human pulmonary artery smooth muscle cell size, contractile protein expression, and contractile function, as well on the roles of glycogen synthase kinase (GSK)-3beta and p70 ribosomal S6 kinase (p70S6K), two proteins involved in translational control, in this process. Unlike epidermal growth factor, BMP-4, TGF-beta1, 5-HT, and ET-1 each increased smooth muscle cell size, contractile protein expression, fractional cell shortening, and GSK-3beta phosphorylation. GSK-3beta inhibition by lithium or SB-216763 increased cell size, protein synthesis, and contractile protein expression. Expression of a non-phosphorylatable GSK-3beta mutant blocked BMP-4-, TGF-beta1-, 5-HT-, and ET-1-induced cell size enlargement, suggesting that GSK-3beta phosphorylation is required and sufficient for cellular hypertrophy. However, BMP-4, TGF-beta1, 5-HT, and ET-1 stimulation was accompanied by an increase in serum response factor transcriptional activation but not eIF2 phosphorylation, suggesting that GSK-3beta-mediated hypertrophy occurs via transcriptional, not translational, control. Finally, BMP-4, TGF-beta1, 5-HT, and ET-1 treatment induced phosphorylation of p70S6K and ribosomal protein S6, and siRNAs against p70S6K and S6 blocked the hypertrophic response. We conclude that mediators implicated in the pathogenesis of PAH induce pulmonary arterial smooth muscle hypertrophy. Identification of the signaling pathways regulating vascular smooth muscle hypertrophy may define new therapeutic targets for PAH.

A morphometric study of hypertrophy of the bronchial smooth muscles and its distribution in bronchial asthma

A morphometric study of hypertrophy of the bronchial smooth muscles and its distribution in bronchial asthma

Assessing the validity of a novel model of vertebral artery type of cervical syndrome induced by injecting sclerosing agent next to transverse process of cervical vertebra

The efficacy of injecting sclerosing agent next to transverse process of cervical vertebra to induce vertebral artery type of cervical syndrome (CSA) was observed. Twenty rabbits were randomly divided into two groups: the model group and the control group. The rabbits in the model group were injected with sclerosing agent next to transverse process of cervical vertebray, on the contrary, the rabbits in the control group were injected with nothing. Transcranial Doppler (TCD) was used to detect the average speed of blood (Vm), pulsatility index (Pi) and the resistant index (Ri) of the vertebral artery, hematoxylin and eosin (HE) staining was used to observe the morphological changes, and immunohistochemistry was used to detect the expression of alpha-smooth muscle actin (alpha-SMA) and matrix metalloproteinase-2(MMP-2). TCD showed increased Pi, Ri and decreased Vm in the model group (P<0.05) compared with the control group. HE staining revealed hyperplasia and hypertrophied smooth muscle cells in the model group (P<0.05). Immunohistochemistry displayed up-regulation of alpha-SMA and MMP-2 in the model group (P<0.05). It was concluded that injecting sclerosing agent next to transverse process of cervical vertebra induces remodeling of vertebral artery in rabbits, suggesting it is a practical method to establish CSA animal model.

Inhalational Therapy for Pulmonary Arterial Hypertension: Current Status and Future Prospects

This review summarizes the pathophysiology and current therapeutic and drug delivery strategies for pulmonary arterial hypertension (PAH), a rare but devastating disorder of the pulmonary circulation affecting 50,000 to 100,000 persons in the United States. Chief clinical features of PAH include increased mean pulmonary arterial pressure (>25 mm Hg) and right ventricular and smooth muscle hypertrophy. A wide variety of agents have been studied for use as anti-PAH drugs, including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors, to name a few. However, a major shortcoming of anti-PAH medications is their short half-lives, requiring them to be administered via parenteral routes, which lead to undesirable side effects, including systemic vasodilation. Inhalational delivery of anti-PAH drugs provides an attractive alternative to conventional routes, with ease of administration and minimal systemic vasodilation. Recently, the U.S. Food and Drug Administration approved inhalable iloprost (Ventavis®), a prostacyclin analogue, for PAH treatment. Other drugs being studied for their potential in inhalable PAH therapy include PGE1, treprostinil, vasoactive intestinal peptide, and fasudil. Controlled-release inhalable delivery systems for anti-PAH medications have also been proposed to facilitate long-term and selective vasodilation of pulmonary arteries. Extensive studies are warranted to develop safe and effective drug delivery systems that will provide a better quality of life to patients.

Role of arginase in asthma: potential clinical applications

Allergic asthma is a chronic disease with significant morbidity and mortality. It affects 300 million people worldwide and absorbs a significant amount of the healthcare budget. The predisposition to asthma is dictated by complex genetic regulation, and the asthmatic inflammation itself is characterized by the interplay of various local cells of the bronchial tree and invading inflammatory immune cells. The clinical problems of asthma are owing to intermittent airway hyper-responsiveness that can become chronic in the course of the disease. Histopathologically, infiltration with a variety of inflammatory cells, smooth muscle cell hyperplasia and hypertrophy, goblet cell hyperplasia and subepithelial fibrosis are found in asthmatic inflammatory tissue. This special report sets out to review data on the role of the enzyme arginase and L-arginine metabolism as a unifying element of asthma pathophysiology and as a potential target for future clinical asthma treatment.

Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy

Despite our understanding that medial smooth muscle hypertrophy is a central feature of vascular remodeling, the molecular pathways underlying this pathology are still not well understood. Work over the past decade has illustrated a potential role for the multifunctional calmodulin-dependent kinase CaMKII in smooth muscle cell contraction, growth, and migration. Here we demonstrate that CaMKII is enriched in vascular smooth muscle (VSM) and that CaMKII inhibition blocks ANG II-dependent VSM cell hypertrophy in vitro and in vivo. Specifically, systemic CaMKII inhibition with KN-93 prevented ANG II-mediated hypertension and medial hypertrophy in vivo. Adenoviral transduction with the CaMKII peptide inhibitor CaMKIIN abrogated ANG II-induced VSM hypertrophy in vitro, which was augmented by overexpression of CaMKII-delta2. Finally, we identify the downstream signaling components critical for ANG II- and CaMKII-mediated VSM hypertrophy. Specifically, we demonstrate that CaMKII induces VSM hypertrophy by regulating histone deacetylase 4 (HDAC4) activity, thereby stimulating activity of the hypertrophic transcription factor MEF2. MEF2 transcription is activated by ANG II in vivo and abrogated by the CaMKII inhibitor KN-93. Together, our studies identify a complete pathway for ANG II-triggered arterial VSM hypertrophy and identify new potential therapeutic targets for chronic human hypertension.

Protection of Angiotensin II–Induced Vascular Hypertrophy in Vascular Smooth Muscle–Targeted Receptor Activity-Modifying Protein 2 Transgenic Mice

The vasodilator and vascular regulatory peptide adrenomedullin (AM), a member of the calcitonin gene-related peptide family of peptides, is predicted to play a pivotal protective role in cardiovascular dysfunction. The principle AM (AM1) receptor is composed of a G protein-linked calcitonin receptor-like receptor and a receptor activity-modifying protein (receptor activity-modifying protein 2). There is little knowledge of the receptors via which AM acts in diseases. Using smooth muscle-targeted receptor activity-modifying protein 2 transgenic mice with increased vascular density of functional AM1 receptors, we demonstrate that receptor activity-modifying protein 2 transgenic mice are not protected against angiotensin II-induced hypertension or cardiac hypertrophy. However, vascular hypertrophy, together with vascular cell adhesion molecule 1 and monocyte chemotactic protein 1 expression, is significantly reduced in the aortic walls of transgenic mice, as determined by histological techniques. This indicates that the AM1 vascular smooth muscle receptor can mediate local protection in vivo. This is supported by proliferation studies in cultured smooth muscle cells. By comparison, levels of hypotension and inflammation in a shock model were similar to those in wild-type mice. Thus, a role of the AM1 receptor in the vasoactive component could not be detected, and evidence is provided to show that the hypotensive response to AM is subject to desensitization in vivo. The finding that the vascular smooth muscle AM1 receptor acts at a local level to protect against hypertension-induced vascular hypertrophy and inflammation provides evidence that targeting this receptor may be a beneficial therapeutic approach.

Severe asthma: a consequence of over exuberant repair?

Severe asthma: a consequence of over exuberant repair?

UP-3.055: Effects of Bladder Trabeculation Grade on the Result after Transurethral Resection of the Prostate

Bladder outlet obstruction induced by benign prostatic hypertrophy (BPH) contributes to form the bladder trabeculation affecting smooth muscle hypertrophy, fibrosis. This study was designed to find out the effects of bladder trabeculation grade on the outcome after the transurethral resection of the prostate (TURP).

Alterations in Caveolin Expression and Ultrastructure After Bladder Smooth Muscle Hypertrophy

Partial bladder outlet obstruction in male rabbits causes detrusor smooth muscle hypertrophy and voiding dysfunction similar to that observed in men with benign prostate hyperplasia. Using this model, we analyzed the protein expression and ultrastructure of caveolae and the intermediate size filament in detrusor smooth muscle following partial bladder outlet obstruction induced hypertrophy. Detrusor smooth muscle sections from bladder body were processed for immunofluorescence and electron microscopy. Western analysis was performed to determine the expression of caveolin isoform-1, 2 and 3, and intermediate size filament proteins. Detrusor smooth muscle cells from both normal and hypertrophied bladders contain orderly arrays of thick and thin myofilaments, interspersed with dense bodies. In addition, there was an increase in intermediate size filaments in the hypertrophic detrusor smooth muscle cells. The dense plaques in the inner membrane of hypertrophied detrusor smooth muscle were longer than those of the control. Detrusor smooth muscle from hypertrophied bladder revealed a decreased number of caveolae and a lack of their orderly distribution at the plasma membrane. Western blotting showed decreased expression of caveolin-1, 2 and 3 in hypertrophied detrusor smooth muscle. Caveolae serve as platforms for proteins and receptors that have a role in signal transduction. The decreased number of caveolae and caveolin protein expression in hypertrophied detrusor smooth muscle might contribute to alterations in signal transduction pathways that regulate the downstream effects of agonist induced contraction, including calcium sensitization, observed in obstructed bladder. In addition, the increased number of intermediate size filaments in the hypertrophied detrusor smooth muscle is likely to alter the cytoskeletal structure and affect the cellular transmission of passive and/or active force.

Endothelin signalling in arterial smooth muscle is tightly regulated by G protein-coupled receptor kinase 2

AimsProlonged endothelin (ET) receptor signalling causes vasoconstriction and can lead to hypertension, vascular smooth muscle hypertrophy, and hyperplasia. Usually, G protein-coupled receptor signalling is negatively regulated by G protein-coupled receptor kinases (GRKs), preventing prolonged or inappropriate signalling. This study investigated whether GRKs regulate ET receptor contractile signalling in adult Wistar rat mesenteric arterial smooth muscle cells (MSMCs).Methods and resultsET-1-stimulated phospholipase C (PLC) activity and changes in [Ca2+]i were assessed using confocal microscopy in rat MSMCs transfected with the pleckstrin-homology domain of PLCδ1 (eGFP-PH) and loaded with Fura-Red. ET-1 applications (30 s) stimulated transient concentration-dependent eGFP-PH translocations from plasma membrane to cytoplasm and graded [Ca2+]i increases. ET-1-mediated PLC signalling was blocked by the type A endothelin receptor (ETAR) antagonist, BQ123. To characterize ETAR desensitization, cells were stimulated with a maximally effective concentration of ET-1 (50 nM, 30 s) followed by a variable washout period and a second identical application of ET-1. This brief exposure to ET-1 markedly decreased ETAR responsiveness to re-challenge, and reversal was incomplete even after increasing the time period between agonist challenges to 60 min. To assess GRK involvement in ETAR desensitization, MSMCs were co-transfected with eGFP-PH and catalytically inactive D110A,K220RGRK2, D110A,K220RGRK3, K215RGRK5, or K215RGRK6 constructs. D110A,K220RGRK2 expression significantly attenuated ETAR desensitization, whereas other constructs were ineffective. Small interfering RNA-targeted GRK2 depletion equally attenuated ETAR desensitization. Finally, immunocyotchemical data showed that ETAR activation recruited endogenous GRK2 from cytoplasm to membrane.ConclusionThese studies identify GRK2 as a key regulator of ETAR responsiveness in resistance arteries, highlighting the potential importance of this GRK isoenzyme in regulating vasoconstrictor signalling pathways implicated in vascular disease.

Infantile hypertrophic pyloric stenosis: evaluation of three positional candidate genes, TRPC1, TRPC5 and TRPC6, by association analysis and re-sequencing

Infantile hypertrophic pyloric stenosis (IHPS) is the most common inherited form of gastrointestinal obstruction in infancy with a striking male preponderance. Infants present with vomiting due to gastric outlet obstruction caused by hypertrophy of the smooth muscle of the pylorus. Two loci specific to extended pedigrees displaying autosomal dominant inheritance have been identified. A genome scan identified loci on chromosomes 11q14-q22 and Xq23-q24 which are predicted to be responsible for a subset of smaller families with IHPS demonstrating non-Mendelian inheritance. The two linked chromosomal regions both harbour functional candidate genes which are members of the canonical transient receptor potential (TRPC) family of ion channels. Both TRPC5 (Xq23-q24) and TRPC6 (11q14-q22) have a potential role in smooth muscle control and hypertrophy. Here, we report suggestive evidence for a third locus on chromosome 3q12-q25 (Zmax = 2.7, p < 0.004), a region which harbours a third TRPC gene, TRPC1. Fine mapping of all three genes using a tagSNP approach and re-sequencing identified a SNP in the promoter region of TRPC6 and a missense variant in exon 4 of TRPC6 which may be putative causal variants.

Bladder Stromal Loss of Transforming Growth Factor Receptor II Decreases Fibrosis After Bladder Obstruction

Transforming growth factor-beta is a potent stimulator of extracellular matrix production. Several studies show that loss of transforming growth factor-beta signaling decreases kidney, liver and lung fibrosis. However, the role of transforming growth factor-beta signaling in bladder fibrosis is not entirely understood. We investigated the effect of stromal loss of such signaling in mice after partial bladder outlet obstruction. We performed partial bladder outlet obstruction by urethral ligation in 5-week-old female Tgfbr2(colTKO) mice. These mice were compared to WT mice with partial bladder outlet obstruction and to WT nonobstructed controls. After 4 weeks and before sacrifice urodynamics were performed. Bladder tissue was harvested, and p-Smad2 and collagen (Masson's trichrome) staining were performed. Bladder compliance was increased in partially obstructed Tgfbr2(colTKO) mice and decreased in partially obstructed WT mice. The latter had increased smooth muscle hypertrophy and increased collagen deposition between smooth muscle bundles compared to those in Tgfbr2(colTKO) mice and nonobstructed controls. Transforming growth factor-beta responsive collagen promoter activity was significantly decreased in Tgfbr2 knockout bladder stromal cells vs WT stromal cells. Stromal loss of transforming growth factor-beta signaling decreased collagen deposition after partial bladder outlet obstruction. In contrast to collagen production by recruited macrophages, stromal transforming growth factor-beta signaling appears to be the primary source of fibrosis after partial bladder outlet obstruction. These findings further support the hypothesis that manipulating transforming growth factor-beta signaling in bladder stromal cells would provide a future avenue for neuropathic bladder and bladder fibrosis treatment.

P70 Ribosomal S6 Kinase Is Required for Airway Smooth Muscle Cell Size Enlargement but Not Increased Contractile Protein Expression

We examined the contribution of p70 ribosomal S6 kinase (p70S6K) to airway smooth muscle hypertrophy, a structural change found in asthma. In human airway smooth muscle cells, transforming growth factor (TGF)-beta, endothelin-1, and cardiotrophin-1 each induced phosphorylation of p70S6K and ribosomal protein S6 while increasing cell size, total protein synthesis, and relative protein abundance of alpha-smooth muscle actin and SM22. Transfection of myocytes with siRNA against either p70S6K or S6, or infection with retrovirus encoding a kinase-dead p70S6K, reduced cell size and protein synthesis but had no effect on contractile protein expression per mg total protein. Infection with a retrovirus encoding a constitutively active, rapamycin-resistant (RR) p70S6K increased cell size but not contractile protein expression. siRNA against S6 decreased cell size in myocytes expressing RR p70S6K. Finally, TGF-beta treatment, but not RR p70S6K expression, increased KCl-induced fractional shortening. Together, these data suggest that p70S6K activation is both required and sufficient for airway smooth muscle cell size enlargement but not contractile protein expression. Further, ribosomal protein S6 is required for p70S6K-mediated cell enlargement. Finally, we have shown for the first time in a functional cell system that p70S6K-mediated myocyte enlargement alone, without preferential contractile protein expression, is insufficient for increased cell shortening.

Oxidative Stress and Compartment of Gene Expression Determine Proatherosclerotic Effects of Inducible Nitric Oxide Synthase

Genetic and pharmacological inhibition of inducible nitric oxide synthase (iNOS) decreases atherosclerosis development. Potential proatherogenic effects of iNOS include iNOS mediated oxidative stress and iNOS expression in different cellular compartments. Lesional iNOS can potentially produce nitric oxide radicals (NO), superoxide radicals (O2(-)), or both; these radicals may then react to form peroxynitrite. Alternatively, O2(-) radicals from oxidases co-expressed with iNOS could react with NO to produce peroxynitrite. Therefore, the expression profiles of the genes that modulate the redox system in different iNOS-expressing cell compartments may determine the role of iNOS in atherosclerosis. We used apoE (apoE(-/-)) and apoE/iNOS double knockout (apoE(-/-)/ iNOS(-/-)) mice to assess vascular NO, O2(-), and peroxynitrite formation by electron spin resonance spectroscopy, high performance liquid chromatography, and 3-nitrotyrosine staining. The relevance of the iNOS expressing cell compartment was tested by bone marrow transplantation. We show that iNOS significantly contributes to vascular NO production and itself produces O2(-), leading to peroxynitrite formation in atherosclerotic lesions. Our bone marrow transplantation experiments show that bone marrow derived cells exclusively mediate the proatherosclerotic effects of iNOS in males, while both parenchymal and bone marrow derived iNOS equally contribute to atherosclerosis in females. Moreover, iNOS expression affects vascular remodeling. These findings establish for the first time that the proatherosclerotic effects of iNOS vary with sex in addition to the compartment of its expression.

H-RAS Controls Phenotypic Profiles of Vascular Smooth Muscle Cells and the Pathogenesis of Vascular Proliferative Disorders

See related article, pages 1192–1200 Vascular smooth muscle (VSMC) migration, proliferation, and hypertrophy following physical, chemical, or biological injury are key events in the onset and progression of vascular proliferative disorders, such as atherosclerosis, postangioplasty stenosis, venous bypass graft failure, and transplantation. Under normal conditions, VSMCs exist in a quiescent state of growth that supports contractile function and structural and functional integrity of the vascular wall. Vascular injury disrupts critical cell-cell and cell-matrix interactions, leading to activation of VSMCs. The activated VSMC phenotype is characterized by gradual loss of differentiated characteristics, increased response to chemotactic agents, and uncontrolled proliferation. Not surprisingly, the quest for molecular triggers of VSMC proliferation led investigators to studies of cell cycle control proteins and mitogenic signaling within the vascular wall. Of note are seminal studies examining the signaling cascades of platelet-derived growth factor1,2 and various protooncogenes, including myb ,3,4 myc ,5,6 and H-ras .7,8 H-RAS quickly emerged as a critical convergence point in VSMC mitogenic signaling and was identified as a putative target for pharmacological intervention in vascular proliferative disorders.9 H - and K-ras were first identified as viral oncogenes in Harvey and Kirsten rat sarcomas, respectively.10 Subsequent studies identified a third member, N-ras , as a protooncogene present in various tumor cell lines.11 Studies of the cellular viral ras oncogene counterparts led to the identification of ras protooncogenes as TATA-less, GC-rich genes that encode for 21-kDa proteins with homology to the α subunit of G proteins.12 p21RAS binds guanine nucleotides and possesses intrinsic GTPase activity,13 and mutations at …

Morphologic Evidence Suggestive of Hypertension in Western Gray Kangaroos (Macropus fuliginosus)

Marked renal vascular changes, suggestive of hypertension, were present in adult western gray kangaroos (Macropus fuliginosus) from a single facility over a 14-year period. A subset of these kangaroos also had vague clinical nervous system deficits, including blindness. To characterize the vascular lesions, determine prevalence, and document other changes, case histories and archival tissue sections from 21 adult kangaroos (8 male, 13 female) that died or were euthanatized between 1994 and 2008 were reviewed. Relevant lesions included increased thickness of the renal arteriolar tunica media with smooth muscle hypertrophy and/or hyperplasia, accumulation of extracellular matrix within arterioles, increased vascular tortuosity, and varying degrees of juxtaglomerular hyperplasia. Renal tissue from two more severely affected animals was further examined by transmission electron microscopy, highlighting arteriolar endothelial cell hypertrophy and disruption of the medial architecture. Hypertrophy of arteries and arterioles in other organ systems was also present (3/21), including vessels in the brain and spinal cord of one animal with clinical neurologic signs. Four kangaroos had antemortem retinal detachment, a potential sequel of hypertension in humans and domestic mammals. The cause of these vascular lesions in this mob is uncertain. Lesions were not associated with an infectious disease process, age, underlying renal disease, or thyroid abnormalities. In the absence of other causes, hypertension was a differential. Further investigation into clinical significance and predisposing factors, such as genetics and diet, is warranted.

Bladder outlet obstruction accelerates bladder carcinogenesis

To examine the correlation between partial bladder outlet obstruction (PBOO) and bladder carcinogenesis. Female Wistar rats (6 weeks old) were divided into three groups of 10 each: group 1 was exposed to n-butyl-n-butanol nitrosamine (BBN, a carcinogen) in drinking water for 8 weeks; group 2 had PBOO induced surgically after exposure to BBN for 8 weeks; group 3 had a sham operation and the rats drank normal water (control group). After 20 weeks, all of the rats were killed humanely and their bladders analysed. There were no significant differences in body weight among the groups. The bladder weight of group 2 was significantly greater than either group 1 or group 3. Histopathologically, bladder smooth muscle hypertrophy was the major cause of the increased bladder weight for group 2. In group 2 there were increases in bladder wall thickness and many nipple-shaped urothelial tumours. Basic fibroblast growth factor and hypoxia-inducible factor-1alpha expression were significantly greater in group 2 than in groups 1 and 3. Exposure of the bladder to carcinogens during bladder hyperplasia and hypertrophy induced by PBOO results in a greater incidence of superficial bladder carcinoma.

Alpha1‐Adrenoceptor mediated aortic contraction involves transactivation of EGF receptor

Prolonged elevation of plasma catecholamines is a risk factor for vascular diseases such as hypertension and atherosclerosis. Catecholamines induce hypertrophy of vascular smooth muscle through alpha1‐adrenoceptors (α1‐ARs). In cell culture this involves the transactivation of epidermal growth factor receptor (EGFR). We hypothesized EGFR transactivation to be involved also in the α1‐AR mediated aortic contraction. Thoracic aorta was isolated from 12‐14 weeks old male Wistar rats. In vitro aortic contractile responses to cumulative doses of phenylephrine (PE) were investigated in the absence and presence of EGFR antagonists AG1478 and DAPH in intact and endothelium‐denuded rings. Involvement of signal transduction pathways was investigated by using heparin and inhibitors of Src, MMP, ERK1/2 and IP3K. AG1478 concentration dependently decreased PE‐induced contractile responses in both intact (pA2=5,52) and denuded (pA2=5,47) rings, as did DAPH. In contrast, AG1478 did not affect contraction response to the thromboxane analog U46619. Blockade of IP3K by wortmannin abrogated the effect of AG1478 on the PE response, whereas heparin and inhibitors of Src, MMP and ERK1/2 did not affect the AG1478 action. α1‐AR mediated contraction of aortic ring involves transactivation of EGFR, most likely via activation of the IP3K pathway and not by shedding of heparin‐binding EGF. This study was supported by GUIDE.